Deubiquitinase OTUD5 Promotes Hepatitis B Virus Replication by Removing K48-linked Ubiquitination of HBV core/precore and Up-regulating HNF4ɑ Expressions through Inhibiting the ERK1/2 /Mitogen-activated Protein Kinase Pathway

Abstract Hepatitis B virus (HBV) infection is a major public health problem worldwide, causing nearly one million deaths annually. OTUD5 is a deubiquitinase associated with cancer development and innate immunity response. However, the regulatory mechanisms of OTUD5 underlying HBV replication need to be deeply elucidated. In the present investigation, we found that HBV induced significant up-regulation of OTUD5 protein in HBV-infected cells. Further study showed that OTUD5 displayed interaction with HBV core/precore, removing their K48-linked ubiquitination chains, and protecting their stability. Meanwhile, overexpression of OTUD5 could inhibit the MAPK pathway, and then increase the expression of HNF4ɑ, and ERK1/2 signaling was required for OTUD5-mediated activation of HNF4α, resulting in the promotion of HBV replication. Together, these data indicate that OTUD5 could inhibit HBV core protein degradation by its deubiquitinase function and promote HBV activity by up-regulating HNF4α expression via inhibition of ERK1/2 pathway. These results might present as a novel therapeutic strategy against HBV infection.